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Northwestern Medicine researchers have uncovered significant insights into how metabolic dysfunction contributes to Parkinson’s disease (PD), according to a recent study published in Nature Communications.
Parkinson’s disease, the second most common neurodegenerative disorder, is characterized by the progressive loss of dopaminergic neurons in the brain’s movement control center. These neurons have high energy demands, making them particularly susceptible to mitochondrial dysfunction, which leads to oxidative stress and cellular damage.
“Prior studies have revealed mitochondrial dysfunction to be a driver of Parkinson’s disease, but the molecular mechanisms through which mitochondrial metabolic pathways contribute to the pathogenesis of PD have been largely unknown,” said Dr. Dimitri Krainc, senior author of the study and chair of the Ken and Ruth Davee Department of Neurology at Northwestern Medicine.
Investigating the Role of CHCHD2 in Parkinson’s Disease
A subset of Parkinson’s disease cases is linked to mutations in the CHCHD2 gene, which encodes a mitochondrial protein. To better understand its role, Krainc and his team conducted an extensive metabolomic analysis of purified mitochondria.
Their research revealed that alpha-ketoglutarate dehydrogenase (alpha-KGDH), an enzyme critical for metabolism regulation, was impaired in affected neurons. This impairment led to a breakdown in the conversion of alpha-KG to succinate in the TCA cycle, reducing mitochondrial respiration and ATP production—an essential energy source for cells.
Lipid Peroxidation and Neuronal Damage
Further investigation demonstrated that disruption of this metabolic pathway resulted in increased lipid peroxidation. This process damages cellular membranes and may contribute to neuronal death, a hallmark of Parkinson’s disease.
In an encouraging development, researchers found that treating affected neurons with lipoic acid reduced lipid peroxidation and prevented the accumulation of alpha-synuclein, a protein associated with Parkinson’s disease progression. These findings suggest that metabolic interventions could potentially offer therapeutic benefits for Parkinson’s patients.
Future Directions in Parkinson’s Research
“The findings highlight an important role of dysregulated mitochondrial metabolism in the pathogenesis of Parkinson’s disease and suggest a therapeutic approach through targeting of alpha-ketoglutarate dehydrogenase,” Krainc noted.
Moving forward, Krainc and his team plan to continue exploring this metabolic pathway in other forms of Parkinson’s disease to develop targeted treatment strategies.
Reference:
Ge Gao et al., Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson’s disease models, Nature Communications (2025). DOI: 10.1038/s41467-025-57142-9
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Individuals seeking medical guidance should consult a healthcare professional.
